Activation of the PI3K/Akt/mTOR and MAPK signaling pathways in response to acute solar-simulated light exposure of human skin

Yira Bermudez, Steven P Stratton, Clara N Curiel, James A Warneke, Chengcheng Hu, George T. Bowden, Sally E Dickinson, Zigang Dong, Ann M. Bode, Kathylynn Saboda, Christine A. Brooks, Emanuel F. Petricoin, Craig A. Hurst, David S Alberts, Janine G Einspahr

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers.

Original languageEnglish (US)
Pages (from-to)720-728
Number of pages9
JournalCancer Prevention Research
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

Ultraviolet Rays
Phosphatidylinositol 3-Kinases
Light
Skin
Serine
Skin Neoplasms
Threonine
Phosphorylation
Sunburn
S 6
Proteins
Nucleosomes
Solar System
Histones
Tyrosine
Volunteers
Immunohistochemistry
Apoptosis
Biopsy
Costs and Cost Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of the PI3K/Akt/mTOR and MAPK signaling pathways in response to acute solar-simulated light exposure of human skin. / Bermudez, Yira; Stratton, Steven P; Curiel, Clara N; Warneke, James A; Hu, Chengcheng; Bowden, George T.; Dickinson, Sally E; Dong, Zigang; Bode, Ann M.; Saboda, Kathylynn; Brooks, Christine A.; Petricoin, Emanuel F.; Hurst, Craig A.; Alberts, David S; Einspahr, Janine G.

In: Cancer Prevention Research, Vol. 8, No. 8, 01.08.2015, p. 720-728.

Research output: Contribution to journalArticle

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abstract = "The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers.",
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AU - Warneke, James A

AU - Hu, Chengcheng

AU - Bowden, George T.

AU - Dickinson, Sally E

AU - Dong, Zigang

AU - Bode, Ann M.

AU - Saboda, Kathylynn

AU - Brooks, Christine A.

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AU - Hurst, Craig A.

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